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Oculocutaneous tyrosinemia/tyrosine aminotransferase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Tyrosine aminotransferase normally converts tyrosine to p-hydroxyphenylpyruvic acid (see Figure 21.1). It is the rate-limiting step in the metabolism of tyrosine. The enzyme is highly regulated. Transcription is induced by glucocorticoids and cyclic AMP [46]. It is also developmentally regulated and human neonatal levels of activity are low [47]. The enzyme is a dimer that is phosphorylated and acetylated at its N-terminus. Pyridoxal phosphate is bound to lysine in the enzyme protein [48]. The activity of the enzyme has been measured in the liver of patients [1, 15, 29, 48–50] and found to be low.
Pharmacokinetic-Pharmacodynamic Correlations of Corticosteroids
Published in Hartmut Derendorf, Günther Hochhaus, Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
Helmut Möllmann, Stefan Baibach, Günther Hochhaus, Jürgen Barth, Hartmut Derendorf
Adapting this approach Boudinot et al.149 used the time course of the hepatic enzyme tyrosine aminotransferase (TAT), a classic gene-mediated effect,148 as a biological response to derive a pharmacokinetic-pharmacodynamic model for receptor/gene-mediated corticosteroid effects. He measured various biophases, such as the total plasma, free non-protein bound plasma, CBG-free plasma, and liver P concentration, as well as the free hepatic cytosolic corticosteroid receptors, as a function of time after P administration in adrenalectomized rats. Although this approach described the TAT activity adequately, the model was not able to ascertain which of the above-mentioned biophases best reflects the corticosteroid-receptor interaction. In addition, a simultaneous fitting of receptor and TAT data was not possible. An improved second-generation model150 included the latter problem (Figure 19). It provided for coupling of receptor and TAT data and can describe recycling of receptors between cytosol and nucleus and the return of cytosolic receptors to baseline after corticosteroid elimination.
Biochemical Effects in Animals
Published in Stephen P. Coburn, The Chemistry and Metabolism of 4′-Deoxypyridoxine, 2018
Rosen et al.424 examined the effects of deoxypyridoxine (100 mg/kg body weight) on liver tyrosine aminotransferase, amino acid uptake, and synthesis of nucleic acids and protein in rats. In B6 deficiency, tyrosine aminotransferase activity was reduced to 48% of the control value and addition of deoxypyridoxine caused a further reduction to about 17% of the control value. Addition of pyridoxal phosphate to the assay increased activity by 63, 137, and 388% in the control, B6-deficient, and B6-deficient plus deoxypyridoxine groups. However, even the addition of pyridoxal phosphate failed to equalize the tyrosine transaminase activity in the three groups suggesting that the groups differed in the amount of apoenzyme as well as the amount of cofactor present.
Systemic oscillator-driven and nutrient-responsive hormonal regulation of daily expression rhythms for gluconeogenic enzyme genes in the mouse liver
Published in Chronobiology International, 2019
Akiko Taira, Emiko Arita, Eriko Matsumoto, Ayano Oohira, Katsuro Iwase, Takaki Hiwasa, Koutaro Yokote, Shigenobu Shibata, Masaki Takiguchi
Regulation of gluconeogenesis is largely conducted through transcription of genes for gluconeogenic enzymes such as the glucose-6-phosphatase (G6Pase), catalytic subunit (G6pc) (Hutton and O’Brien 2009), phosphoenolpyruvate carboxykinase (PEPCK), cytosolic form (Pck1) (Croniger et al. 2002), as well as for amino acid-metabolizing enzymes, including tyrosine aminotransferase (TAT) (Tat) (Boshart et al. 1993; Nitsch et al. 1993) which provides carbon skeletons essential for gluconeogenesis. Daily rhythms in mRNA levels for Pck1 and Tat were first detected by in situ hybridization and RNA blot analyses (Bartels et al. 1990), and for G6pc by microarray analysis (Storch et al. 2002). To supply glucose adequately, the expression rhythms of gluconeogenic enzyme genes must be precisely regulated in response to nutritional changes such as prolonged fasting and day-to-day variations in dietary nutrient composition.
Research on the hepatotoxicity mechanism of citrate-modified silver nanoparticles based on metabolomics and proteomics
Published in Nanotoxicology, 2018
Jiabin Xie, Wenying Dong, Rui Liu, Yuming Wang, Yubo Li
Tyrosine, a major component of aromatic amino acids, is mainly metabolized in the cytoplasm of liver cells and is well-correlated with liver damage (Suzuki et al. 1998). AgNP-cit acted on the body, decreasing the level of tyrosine and disrupting tyrosine metabolism, which may lead to liver damage. Tyrosine aminotransferase (Tat) has a significant effect on tyrosine catabolism and was down-regulated due to the toxic effects of AgNP-cit. This led to accumulation of tyrosine and its by-products, which may damage the liver (Fu et al. 2010). Tryptophan has demonstrated an extraordinary ability to reduce the levels of proinflammatory cytokines in the treatment of liver disease (Li et al. 2016). In this study, the level of tryptophan was significantly reduced due to AgNP-cit, resulting in its decreased ability to reduce proinflammatory cytokine levels, ultimately inducing inflammation liver damage.
A patent review of anticancer glucocorticoid receptor modulators (2014-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Marianna Lucafò, Martina Franzin, Giuliana Decorti, Gabriele Stocco
All the compounds are subjected to assays to measure their ability to bind the GR, and the test used is direct binding assays as well as competitive binding assays [83–85]. Compounds that have demonstrated the desired binding affinity for the GR are further tested for their ability to inhibit GR-mediated activities; to this aim, the tyrosine aminotransferase assay, that assesses the capability of the compound to inhibit the induction of tyrosine aminotransferase activity by dexamethasone is performed and described. Other cell-based assays can be also used; the reduction of signaling activity triggered by the activation of the GR can be evaluated; for example, the upregulation of GRE-dependent genes such as, besides tyrosine aminotransferase, phosphoenolpyruvate carboxykinase, or aromatase, also using specific cell types susceptible to GR activation. Cytotoxicity assays, to evaluate the effects that are not mediated by binding to the GR are also performed. Other assays include the evaluation of the ability of the compounds to inhibit 3 H-thymidine incorporation into DNA in cells stimulated by glucocorticoids, or competition with 3 H-dexamethasone for binding to the GR in an hepatoma cell line [86], or the ability to inhibit the nuclear binding of the 3 H-dexamethasone-GR complex [87]. In addition, to discriminate between glucocorticoid agonists and modulators, receptor binding kinetics can be evaluated [88]. An assay using the thymocytes of adrenalectomized rats incubated with dexamethasone and the test compounds, that measures the incorporation of 3 H thymidine into polynucleotides can also be employed [89,90]. This first step determines if the compound is a glucocorticoid receptor modulator.